Research

We use molecular genetic, electrophysiological and behavioral studies in mouse to understand itch and pain.

This approach to gaining insight into the nervous system is compelling because pain and itch, which induce innate spinal reflexes, are likely to be mediated by genetically-encoded circuits that may be tractable for study. Furthermore, as we discover how activity drives adaptive changes in the excitability of circuits that mediate itch and pain, we may uncover principles of plasticity that have broad application through the nervous system.

Background

Itch and pain are sensory modalities that alert the organism to potential harm and trigger responses—scratching and withdrawal, respectively—that protect the body by separating it from harmful agents. These responses are initiated when noxious stimuli activate primary sensory neurons in the periphery, which convey this information to the spinal cord. Next, neural circuits within the dorsal horn of the spinal cord process and modulate this information prior to relaying it to the brain.

Unfortunately, these circuits are almost completely uncharacterized, despite a pressing need to understand how their dysfunction can lead to chronic pathological conditions. Recent studies have supported the idea pain and itch are mediated by distinct neural circuits; however, the neurons involved are almost completely unknown. In addition, while it is clear that these aversive sensations inhibit one another, the neural basis for this phenomenon is unclear. Thus, there is a fundamental gap in our understanding of the basic wiring and logic of the spinal circuits that mediate pain and itch.

What we are doing

Loss of B5-I gives rise to pathological itch

Our lab uses transcription factors, such as Bhlhb5, Bhlhb4 and Prdm8, as entry points to study the development and function of neural circuits underlying pain and itch. For instance, our work has identified a subset of inhibitory neurons (which we term B5-I neurons) that are required for normal itch sensation; mice lacking these neurons suffer from persistent pathological itch. This work provides the first evidence implicating a loss of inhibitory neurons within the dorsal horn in pathological itch (Fig. 1).

Furthermore, B5-I neurons are the first component of an itch circuit to be labeled genetically, and so studying these neurons provides us with a unique opportunity to unravel itch circuits. We are now using this molecular handle to investigate the development of B5-I neurons and understand how they regulate itch. Next, we will extend our studies of the neural coding of aversive somatosensation, using circuit mapping, axon tracing, and optogenetics to functionally dissect the underlying circuits.

Significance

Improved understanding of the neural basis of pain and itch is of clinical relevance to millions of people worldwide that suffer from clinical conditions, particularly chronic pain, that result from of maladaptive changes in neural circuitry.